TWI906211B - Pharmaceutical compositions for use in treating pain - Google Patents

Abstract

Provided is a pharmaceutical composition for use in treating postsurgical pain. The pharmaceutical composition comprises a lipid-based complex. The lipid-based complex comprises an amide-type anesthetic and at least one lipid, wherein a molar ratio of the amide-type anesthetic to the at least one lipid of the lipid-based complex is at least 0.5:1. The total amount of the amide-type anesthetic is at least 1.5 to 5 times of a standard therapeutic dose for treating postsurgical pain with the amide-type anesthetic to achieve an improved pain control with desired prolonged analgesic effect.

Description

Pharmaceutical components used to treat pain.

This disclosure relates to the use of acetamide anesthetics in pain control. This disclosure relates to methods of pain control.

Local anesthetics are widely used for surgical anesthesia and postoperative analgesia because they reversibly inhibit voltage-gated sodium channels and block action potentials in nerve fibers. However, at high plasma concentrations, these anesthetics can also interact with other ion channels, causing acute neurotoxicity, cardiotoxicity, and allergic reactions. Local anesthetic systemic toxicity (LAST) remains a potential and potentially fatal complication of all local anesthetics, regardless of the route of administration.

Ropivacaine, a pure S(-) isomer amide local anesthetic, was introduced in 1996 and approved by the Food and Drug Administration (FDA) in 2000 under the brand name ^Naropin® . It has relatively low lipophilicity and motor block, and because its cardiotoxicity is lower than bupivacaine ( ^Marcaine® ), ropivacaine also has a wider safety margin. ^Naropin® can be administered via various routes of injection, including spinal anesthesia, epidural anesthesia, regional block, and local infiltration. Despite its many advantages over other local anesthetics, 0.5% ^Naropin® (ropivacaine hydrochloride injection 200 mg) provides only about 6 to 8 hours of anesthesia after a single administration via wound infiltration. This is insufficient to cover most of the postoperative recovery period, especially the critical first 3 days.

Local anesthetics have limitations due to their short duration of action and the risk of systemic toxicity. Infiltration administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and local anesthetics (e.g., ropivacaine hydrochloride) is also widely used for postoperative pain management. However, some potential safety concerns remain regarding the use of NSAIDs, and the duration of postoperative pain relief from local anesthetics is typically only about 8 hours. The medical goal is to relieve acute postoperative pain during the critical 2 to 4 days postoperatively without the use of opioids. Therefore, there remains an unmet medical need for a safer and more effective method of postoperative pain management that provides a single-dose, periphery-based, long-lasting, non-opioid drug.

Whether administered via continuous infusion or repeated bolus, there is a high risk of reaching toxic plasma concentrations or causing local nerve damage when using local anesthetics to achieve prolonged blockade. Evidence supporting the neurotoxicity of local anesthetics comes from analyses of the persistence of sensory abnormalities after injection. The severity of sensory abnormalities is related to the duration of sensory impairment. While in most cases the affected nerves recover spontaneously after a period of time, in some cases, such undesirable effects may be prolonged and last for months, or even prevent complete nerve recovery.

There remains an unmet need for improved use of ropivacaine or other acetamide anesthetics in pain management to achieve both desired prolonged anesthetic effects and beneficial, effective pain control. The compositions and methods disclosed herein address these and other needs.

This disclosure provides methods for treatment using acetamide anesthetics, such as those disclosed herein, with specific dosage ranges and administration schedules, exhibiting prolonged effects in pain control. In particular, this disclosure pertains to pharmacologically active agents, compositions, methods, and/or administration schedules that offer certain advantages over currently used and/or known in the art, including the ability to achieve equivalent pain control or anesthetic effects with lower frequency or dosage, and thus reducing undesirable effects of acetamide anesthetics in individuals with such needs. These advantages will be more clearly illustrated in the following further description.

This disclosure provides a sustained-release anesthetic composition, or a method for preparing the sustained-release anesthetic composition, which utilizes freeze-drying (e.g., one-step lyophilization) to obtain a lipid cake comprising an acetamide anesthetic and at least one lipid, wherein the acetamide anesthetic in the lipid-based complex has a molar ratio of at least 0.5:1 to the at least one lipid, followed by hydration of the lipid cake with a pharmaceutically acceptable buffer solution to obtain the sustained-release anesthetic composition. This sustained-release anesthetic composition provides rapid anesthetic onset, prolonged duration of local anesthesia, and minimal toxicity.

On one hand, the anesthetic composition is a pharmaceutical composition used to treat postoperative pain in individuals with such needs. The pharmaceutical composition according to this disclosure comprises: a lipid-based complex having an acetamide anesthetic and at least one lipid, wherein the molar ratio of the acetamide anesthetic to the at least one lipid in the lipid-based complex is at least 0.5:1, and the total amount of the acetamide anesthetic in the pharmaceutical composition is at least 1.5 to 5 times the standard therapeutic dose of the acetamide anesthetic. The total amount of the acetamide anesthetic in the pharmaceutical composition may range from about 3 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, and optionally, from about 380 mg, about 475 mg, about 570 mg, or may range from about 3 mg to about 300 mg, from about 10 mg to about 250 mg, and optionally, from about 50 mg, about 152 mg, about 190 mg, or about 228 mg. In some specific instances, the amount of the acetamide anesthetic in the pharmaceutical composition is at least 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 to 5 times the standard therapeutic dose of the acetamide anesthetic. Other usable acetamide anesthetics include lidocaine, bupivacaine, mepivacaine, levobupivacaine, their bases, or combinations thereof. In some specific instances, the acetamide anesthetic is bupivacaine, ropivacaine, or their bases.

According to this disclosure, the lipid-based complex comprises a acetamide anesthetic and one or more lipids. In some specific examples, the lipids comprise at least one neutral saturated phospholipid. The at least one neutral saturated phospholipid comprises a saturated fatty acid having a long carbon chain with no more than 18 carbon atoms. In some specific examples, the lipid-based complex is prepared under predetermined conditions for preclinical use, such as room temperature, and contains fatty acids having long carbon chains with 14, 16, and/or 18 carbon atoms.

In some specific instances, the lipid-based complex of the anesthetic composition is formed by hydrating a freeze-dried lipid cake with a pharmaceutically acceptable buffer solution having a pH greater than 5.5. Based on the acid dissociation constant of ropivacaine (which is 8.1), theoretically uncharged ropivacaine constitutes 0.8% of all available ropivacaine at a pH of 6.0. In some specific instances, the lipid cake according to this disclosure is prepared by dissolving nonpolar ropivacaine, phospholipids, and cholesterol in a solvent system (e.g., a tert-butanol monosolvent or a tert-butanol-water cosolvent), followed by removing the solvent system using a freeze-drying technique.

In certain specific instances, the molar ratio (mol _drug : mol _phospholipid ) of the acetamide anesthetic to the phospholipid in the lipid-based complex is at least 0.5:1. This pharmaceutical composition provides sufficient acetamide anesthetic to the individual in need, thereby prolonging the duration of anesthesia following local administration in vivo. Furthermore, the pre-contained acetamide anesthetic, in a free form outside the lipid-based complex, allows for rapid onset of anesthesia and minimizes the maximum plasma concentration ( _Cmax ) of the drug's instantaneous entry into the bloodstream.

On the other hand, this disclosure also provides a method for treating postoperative pain in an individual requiring anesthesia. This method may include administering a pharmaceutical composition as disclosed herein via nerve block, field block, or infiltration anesthesia.

In certain specific cases, postoperative pain is caused by the surgery itself, such as, but not limited to: hernia repair surgery, hallux valgus surgery, urological surgery, orthopedic surgery, obstetric and gynecological surgery, laparoscopic surgery, abdominoplasty, breast surgery, and kidney transplantation procedure (KIX).

On the other hand, this disclosure provides a method for treating postoperative pain. This method may include administering a dose of a pharmaceutical composition as disclosed herein before or after the start of surgery (during surgery), and particularly within approximately half an hour to approximately three hours before the completion of surgery, selectively within half an hour to approximately two hours, and selectively within half an hour to approximately one hour, wherein during the postoperative period, a reduction of at least 2 in pain score according to the Numerical Pain Rating Scale (NPRS) is achieved, wherein this period is at least 48 hours, selectively at least 72 hours, at least 96 hours, or at least 168 hours. The NPRS scale can be measured from 0 to 10, where 0 represents no pain and 10 represents the most severe imaginable pain. In some specific instances, when the components of this disclosure are administered via nerve block or regional block, the components may be administered approximately half an hour to approximately one hour before surgery. In other non-limiting specific instances, when the components of this disclosure are administered via local infiltration (suitable for hernia repair and hallux valgus surgery), the components may be administered during surgery, typically in the final stage of surgery, before the final suturing of the wound.

The other invention objectives, advantages, and novel features of this disclosure will become clearer through the following detailed description in conjunction with the accompanying drawings.

Unless otherwise stated, the following terms used above and throughout this disclosure shall be understood to have the following meanings.

The singular forms “a,” “a kind,” “the,” and “this” used in this article include plural referents unless the context clearly indicates otherwise.

All figures in this article are to be understood as being modified by “approximately”, and when referring to quantities such as amount, duration and such measurable values, it means a variable including ±10% of a specific value, preferably ±5%, even more preferably ±1%, and even more preferably ±0.1%, which applies to describing the required amount of acetamide anesthetics, unless otherwise stated.

As used herein, the term "treat, treating, or treatment" includes preventative (e.g., prophylactic), palliative, and curative methods, uses, or results. The term "treatment" or "treatments" may also refer to a composition or medication. In this application, the term "treating" includes the detection, using known techniques, of symptoms or signs of reduced or alleviated pain of one or more kinds, or the reduction of the use of pain control medications. Pain and its symptoms can be assessed using methods known in the field, including, but not limited to, the 6-point descriptive pain rating scale, the 11-point NPRS, the visual analog scale, the Wisconsin Brief Pain Questionnaire, the Brief Pain Inventory, the McGill Pain Questionnaire and the short-form, and other scoring methods including the Patient Global Assessment (PGA) which incorporates methods for pain management. For an individual, self-report can be used to determine the level of pain, for example, using a rating scale from 0 (no pain) to 10 (most painful). Selectively, after administration of a pharmaceutical composition disclosed herein, functional magnetic resonance imaging (fMRI) may be used to determine a reduction in pain in an individual. For example, if the methods disclosed herein reduce one or more pain symptoms in an individual by at least 1% relative to before treatment or in one or more control groups, this may be considered as a treatment approach. Therefore, the aforementioned reduction may be approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or any of the aforementioned values. An individual's treatment can also be assessed by reducing the use of pain control medications (such as opioids or other anesthetics) and/or reducing side effects associated with such anesthetics (such as opioid-related gastrointestinal symptoms). Additional efficacy questionnaires (such as the postsurgical recovery index) can be used to assess pain and recovery, as well as side effects that may be related to opioid use. In particular, postoperative pain can be acute and/or chronic. Acute pain may be felt immediately or last up to 7 days (e.g., approximately 1, 2, 3, 4, 5, 6, or 7 days after surgery).

The term "subject" can refer to a vertebrate that has (or is at risk of developing) pain or a disease that causes pain, or a vertebrate that is considered to require pain treatment or management. Subjects include all warm-blooded animals, such as mammals (including primates), and preferably humans. Non-human primates are also subjects. The term "subject" includes domesticated animals (such as cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, gerbils, guinea pigs, etc.). Therefore, this article covers veterinary uses and medical formulations.

"Association efficiency (AE)" represents the amount of drug encapsulated in a lipid-based complex, calculated as the ratio of the amount of drug in the isolated lipid-based complex to the total amount of drug in the initial components before separation. The isolated lipid-based complex can be obtained by any method known in the art. In some specific instances, the isolated lipid-based complex is obtained by centrifugation (e.g., conventional centrifugation, density gradient centrifugation, differential centrifugation) or filtration (e.g., dialysis filtration, gel filtration, and membrane filtration).

The term "standard therapeutic dose" can refer to the amount of a specified therapeutic agent that produces the desired effect or result, particularly in a chamber similar to that described in this disclosure, exemplified by drug conversions in poorly perfused tissues such as soft tissues (muscle, fat, and the like) and hard tissues (bone, and the like). Standard therapeutic doses can be determined using techniques commonly used in the art. Appropriate standard therapeutic doses for each indication can be found in relevant anesthetic literature, including but not limited to the United States Pharmacopeia (USP) and approved drug products listed in the Drugs@FDA Library, which is sponsored by the US Food and Drug Administration. The therapeutic dose may be infiltrated or injected into the surgical site. For example, for pain management after hernia surgery, the standard therapeutic dose of ropivacaine hydrochloride solution ( ^Naropin® ) for local infiltration is less than 300 mg, particularly 2 mg to 200 mg. In some specific cases, for pain management after hallux valgus surgery, the standard therapeutic dose of free ropivacaine solution for injection or infiltration is 50 mg. In another specific example, the standard treatment dose of bupivacaine hydrochloride injection (USP) (from Hospira) used in combination with epinephrine (1:200,000) is as high as 225 mg, while the standard treatment dose without epinephrine is 175 mg. The standard treatment dose can be determined according to the type of surgery and can be established using standard techniques in this field. Niacinamide anesthetics

The term "acetamide anesthetic" refers to one or more substances that induce anesthesia in a defined area of an individual by inhibiting nerve excitation or peripheral nerve conduction. A typical acetamide anesthetic structure consists of a lipophilic moiety and a hydrophilic moiety, linked by an -NHCO- bond. Suitable acetamide anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, articaine, and prilocaine and their bases. In some specific instances, the acetamide anesthetic is ropivacaine base. Lipid-based complexes and lipids

The lipid-based complex disclosed herein comprises one or more lipids and a acetamide anesthetic. In one embodiment, the lipid-based complex can be stored long-term after manufacturing, extending the shelf life of the composition. The lipid-based complex may be obtained by hydrating a lipid cake containing one or more lipids and a acetamide anesthetic immediately before clinical use.

The aforementioned lipid cake may contain one or more phospholipids and acetaminophen anesthetics, but no sterols. Additionally, the lipid cake may contain acetaminophen anesthetics, one or more phospholipids, and one or more sterols (e.g., cholesterol), the amount of which is no more than 50% relative to the total lipid content. In some specific examples, the molar percentage of cholesterol based on total lipids is about 0% to 50%, selectively about 33% to 40%. In some specific examples, the molar ratio of phospholipids to cholesterol is 1:1 to 3:1.

Lipid cakes can be prepared by: 1) dissolving one or more lipids and a acetamide anesthetic in a solvent system to form a liquid structure comprising a homogeneous solution of one or more solvents; 2) removing the solvent to solidify the mixture of lipids and acetamide anesthetic. Known techniques can be used to remove the solvent, such as lyophilization. Examples of solvent systems suitable for lyophilization include, but are not limited to, tert-butanol and tert-butanol-water co-solvent systems, and may or may not contain other non-aqueous solvents, such as acetone, acetonitrile, ethanol, n-propanol, isopropanol, n-butanol, methanol, dichloromethane, dimethyl sulfide, or carbon tetrachloride.

In some specific instances, the lipids of the lipid-based complex include one or more phospholipids and cholesterol, and the molar ratio of acetamide anesthetics to phospholipids in the lipid-based complex is at least 0.5:1, selectively between 0.5:1 and 2:1, such as about 0.5:1, about 0.8:1, about 1:1, about 1.2:1, about 1.5:1, about 1.8:1, or about 2:1.

The one or more lipids mentioned are selected from groups consisting of dilipochain lipids (such as phospholipids, diglycerides, and dilipoglycolipids), monolipochain lipids (such as sphingomyelin and glycosphingomyelin), sterols (such as cholesterol and its derivatives), and combinations thereof. Examples of phospholipids according to this disclosure include, but are not limited to: 1,2-dilauroyl- sn -glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl -sn - glycero-3-phosphocholine (DPPC), and 1-palmitoyl-2-stearoyl -sn - glycero-3-phosphocholine (1-palmitoyl-2-stearoyl- sn -glycero-3-phosphocholine ) . 1,2-Palmitoyl-2-oleoyl- sn -glycero-3-phosphatidylcholine (PSPC), 1,2-distearoyl- sn -glycero-3-phosphatidylcholine (DSPC), 1,2-dioleoyl- 1 -sn - glycero-3-phosphatidylcholine (DOPC), hydrogenated soy phosphatidylcholine (HSPC), 1,2-dimyristic - sn- 1,2-dimyristoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), DMPG; 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt), DPPG; 1,2-palmitoyl-2-stearoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG; 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG; 1,2-distearoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), DMPG; 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt), DMPG; 1,2-dipalmitoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG; 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG; 1,2-distearoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG; 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)(sodium salt), PSPG . 1,2-distearoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), DSPG; 1,2-dioleoyl- sn -glycero-3-phospho-(1'-rac-glycerol)(sodium salt), DOPG; 1,2-dimyristoyl- sn -glycero-3-phospho-L-serine (sodium salt ), DMPS; 1,2-dipalmitoyl - sn -glycero-3-phospho-L-serine (sodium salt), DMPS . 1,2-distearoyl- sn -glycero-3-phospho-L-serine (sodium salt), DPPS; 1,2-dioleoyl- sn -glycero-3-phospho-L-serine (sodium salt), DSPS; 1,2-dioleoyl- sn -glycero-3-phospho-L-serine (DOPS); 1,2-dimyristoyl- sn - glycero-3-phosphate (sodium salt), DMPA; 1,2- dipalmitoyl - sn -glycero-3-phosphate (sodium salt), DMPA . 1,2-distearoyl- sn -glycero-3-phosphate (sodium salt), DPPA, 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt), DOPA, 1,2-dipalmitoyl -sn -glycero-3-phosphate ethanolamine (DPPE), 1 -palmitoyl-2-oleoyl -sn -glycero-3-phosphate ethanolamine (POPE), 1,2-distearoyl- sn -glycero-3-phosphate (sodium salt), 1,2-dioleoyl- sn -glycero-3-phosphate (sodium salt ...dioleoyl- sn -glycero-3-phosphate (sodium salt), 1,2-dioleoyl- sn -glycero-3-phosphate (sodium salt), 1,2-dioleoyl- sn -glycer 1,2-distearoyl- sn -glycero-3-phosphoethanolamine (DSPE), 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dipalmitoyl-sn - glycero-3-phospho-(1'-myo-inositol)(ammonium salt) (DPPI), 1,2-distearoyl- sn -glycero-3-phosphoinositol (ammonium salt) (DSPI), 1,2-dioleoyl-sn-glycero-3-phosphoinositol (ammonium salt) (DSPI), 1,2-dioleoyl-sn-glycero-3-phosphoinositol (ammonium salt) (DPPI), 1,2-distearoyl- sn -glycero-3-phosphoinositol (ammonium salt) (DSPI), 1,2-dioleoyl-sn-glycero-3-phosphoinositol (DSPI) (DPPI), 1,2-dipalmitoyl- sn -glycero-3-phosphoinositol (ammonium salt) (DPPI), 1,2-distearoyl- sn -glycero-3-phosphoinositol (ammonium salt ...DSPI), 1,2-dioleoyl-sn-glycero-3-phosphoinositol (DSPI) (DPPI), 1,2-dipalmitoyl-sn-glycero-3-phosphoinositol (ammonium salt) (DPPI), 1,2-dipalmitoyl- sn -glycero-3-phosphoinositol (ammon 1,2-dioleoyl- sn -glycero-3-phospho-(1'-myo-inositol)(ammonium salt), DOPI, cardiolipin, L-α-phosphatidylcholine (EPC), and L-α-phosphatidylethanolamine (EPE).

Examples of phospholipids include, but are not limited to: dimyristylphosphatidylcholine (DMPC), 1,2-dilauryl- sn -glycerol-3-phosphate choline (DLPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), 1,2-dienyl-1- sn -glycerol-3-phosphate choline (DOPC), 1,2-dioleoyl- sn -glycerol-3-phosphoserine (DOPS), dioleoylphosphatidic acid (DOPA), lecithin choline (egg PC), phosphatidylethanolamine (egg PE), 1-palmitoyl-2-oleoyl- sn -Glyceryl-3-phosphate ethanolamine (POPE), cardiolipin and 1,2-dimyristic- sn -glyceryl-3-phosphate (sodium salt) (DMPA).

Suitable phospholipids in this disclosure are saturated phospholipids derived from two saturated long-chain fatty acids, each fatty acid having a long chain of at least 12 carbons, alternatively at least 14 carbons and no more than 20 carbons, alternatively 18 carbons or 16 carbons. In some specific instances, suitable saturated phospholipids in this disclosure may be selected from groups consisting of DLPC, DMPC, and DPPC and combinations thereof.

In some specific instances, the lipid-based complex comprises liposomes and acetamide anesthetics. The liposomes comprise one or more lipids, including suitable phospholipids as disclosed herein, a positively or negatively valent phospholipid, and a defined amount of unsaturated phospholipids, wherein, based on the total phospholipid content, the defined amount of unsaturated phospholipids is less than 10% mole percent, for example: 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. Anesthetic Composition

The terms "anesthetic composition" and "pharmaceutical composition for the treatment of pain" are used interchangeably throughout this document. In some specific instances, an anesthetic composition comprises a lipid-based complex and an unencapsulated local anesthetic. In some specific instances, a lipid-based complex comprises multilamellar vesicles and a local anesthetic encapsulated within the multilamellar vesicles. The terms "encapsulation" or "encapsulation process" refer to the coating, embedding, or bonding of a target drug substance to a bilayer membrane of multilamellar vesicles.

The particle size of the lipid-based complexes disclosed herein can be determined by various methods known in the art. In some specific instances, the lipid-based complexes in the anesthetic composition have an average particle size of not less than 1 micrometer (μm) and selectively greater than 5 micrometers, for example, in the range of 5 to 50 micrometers, or in the range of 10 to 25 micrometers. Additionally, the volume median particle diameter ( _D50 ) of the lipid-based complexes in the anesthetic composition is not less than 1 micrometer; and selectively not less than 5 micrometers, in the range of, for example, 5 to 50 micrometers, 5 to 40 micrometers, 5 to 30 micrometers, 5 to 20 micrometers, or 5 to 15 micrometers. In some specific instances, median diameter ( _D50 ) refers to the particle diameter at which the cumulative percentage of lipid matrix complexes composed of aggregated particles in the cumulative particle size distribution is 50%, which is 5 micrometers, greater than 7 micrometers, or larger. In some specific instances, median diameter ( _D50 ) refers to the particle diameter at which the cumulative percentage of lipid matrix complexes composed of aggregated particles in the cumulative particle size distribution is 50%, which is 25 micrometers or smaller, 20 micrometers or smaller, or 15 micrometers or smaller; and selectively from 5 micrometers to 25 micrometers, 5 micrometers to 20 micrometers, or 5 micrometers to 15 micrometers.

In some specific instances, when the cumulative percentage of the cumulative particle size distribution (D ₉₀ ) of the lipid-based complex of the anesthetic composition is 90%, the particle diameter is not less than 10 micrometers, such as between 10 and 300 micrometers, between 20 and 300 micrometers, between 20 and 200 micrometers, or between 20 and 100 micrometers. Furthermore, the lower limit of D ₉₀ is, for example, but not limited to, 25 micrometers or greater, or 30 micrometers or greater. Additionally, the shape of the agglomerated particles of the lipid-based complex is not particularly limited to improve the bonding efficiency per unit dose.

In some specific instances, pharmaceutical compositions for treating pain include polycystic liposomes, a portion of which contains a nitroglycerin anesthetic, and a portion of which is in a free form, also referred to as a free nitroglycerin anesthetic (unencapsulated). The particle size distribution of the polycystic liposomes containing the nitroglycerin anesthetic in the lipid-based complexes of this disclosure can be determined by various methods known in the art. In some specific instances, the particle size of the polycystic liposomes containing the nitroglycerin anesthetic in the anesthetic composition of this disclosure is not less than 1 micrometer and selectively greater than 5 micrometers, such as between 5 micrometers and 200 micrometers, between 10 micrometers and 100 micrometers, or between 10 micrometers and 50 micrometers. In addition, in the anesthetic composition disclosed herein, the median diameter ( _D50 ) of the lipid matrix complex is not less than 1 micrometer and selectively greater than 5 micrometers, such as between 5 micrometers and 100 micrometers, or between 10 micrometers and 50 micrometers.

In some specific examples, the lipid-based complex is formed by hydrating a lipid cake containing a nitroglycerin anesthetic with a pharmaceutically acceptable buffer solution having a pH greater than 5.5. The resulting anesthetic composition provides a sustained release of the nitroglycerin anesthetic, which may be immediately available or diluted with a buffer solution or other suitable diluent prior to administration. In some specific examples, the buffer solution has a pH range of 5.5 to 8.0, and selectively between 6.0 and 7.5, or between 6.5 and 7.0.

Suitable buffer solutions in this disclosure include, but are not limited to: citrate, acetate, malate, piperazine, succinate, 2-(N-morpholino)ethanesulfonic acid (MES), histidine, bis(2-hydroxyethyl)amino(trihydroxymethyl)methane (bis-tris), phosphate, ethanolamine, N-(2-acetamido)iminodiacetic acid (ADA), carbonate, N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), and 1,4-piperazinediethanesulfonic acid. solutions of acid (PIPES), 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), imidazole, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), triethanolamine, leucine, trihydroxymethylglycine (tris), and glycylglycine. The appropriate buffer solution pH value is selected based on the clinical indications and total injection dose, and the amount of unencapsulated acetamide anesthetic in the composition is adjusted based on the partition coefficient of the anesthetic.

In some specific instances, the buffer solution contains histidine in concentrations ranging from 1 mM to 200 mM, 10 mM to 150 mM, 20 mM to 140 mM, 30 mM to 130 mM, or 40 mM to 120 mM.

In some specific instances, the buffer solution contains phosphoric acid in concentrations ranging from 1 mM to 200 mM, 10 mM to 180 mM, 10 mM to 170 mM, 10 mM to 160 mM, 10 mM to 150 mM, 10 mM to 100 mM, 10 mM to 75 mM, 15 mM to 75 mM, 15 mM to 50 mM, or 20 mM to 50 mM.

The amount of free acetaminophen anesthetics is a function of the binding efficiency (AE) of the lipid-based complex in the anesthetic composition, which can be determined by centrifugation. Mathematically, the amount of untrapped acetaminophen anesthetics can be expressed as follows: A _untrapped = A _total × (1-AE) where A _untrapped is the amount of untrapped acetaminophen anesthetics; A _total is the total amount of acetaminophen anesthetics in the anesthetic composition; and the binding efficiency AE is obtained by dividing the amount of acetaminophen anesthetics in the lipid-based complex by the total amount of acetaminophen anesthetics in the anesthetic composition. The binding efficiency in this disclosure is at least 60%, and selectively, between 60% and 99%, 70% and 95%, and 80% and 90%.

In certain specific instances, the mol _drug to _lipid ratio (D:PL) of the acetamide anesthetic in the lipid-based complex is at least 0.5:1, including but not limited to: 0.7:1, 0.9:1, 1.2:1, 1.4:1 or 2:1. In certain specific instances, the median diameter ( _D50 ) of a group of particles in the lipid matrix complex is not less than 1 micrometer, for example, not less than 5 micrometers, and optionally, the range may be: 5 micrometers to 200 micrometers, 5 micrometers to 190 micrometers, 5 micrometers to 180 micrometers, 5 micrometers to 170 micrometers, 5 micrometers to 160 micrometers, 5 micrometers to 150 micrometers, 5 micrometers to 140 micrometers, 5 micrometers to 130 micrometers, 5 micrometers to 120 micrometers, 5 micrometers to 110 micrometers, 5 micrometers to 100 micrometers, 10 micrometers to 100 micrometers, 12 micrometers to 100 micrometers, 14 micrometers to 100 micrometers, 16 micrometers to 100 micrometers, 18 micrometers to 100 micrometers, or 20 micrometers to 100 micrometers.

The concentration of acetamide anesthetics in anesthetic formulations can exceed 2 mg/mL to achieve clinical therapeutic benefits. Suitable concentrations of acetamide anesthetics include, but are not limited to: at least 10 mg/mL, between 2 mg/mL and 30 mg/mL, between 10 mg/mL and 30 mg/mL, between 10.5 mg/mL and 30 mg/mL, between 11 mg/mL and 30 mg/mL, between 11.5 mg/mL and 30 mg/mL, between 12 mg/mL and 30 mg/mL, between 12.5 mg/mL and 30 mg/mL. The dosages are 0 mg/mL, between 10 mg/mL and 25 mg/mL, between 10.5 mg/mL and 25 mg/mL, between 11 mg/mL and 25 mg/mL, between 11.5 mg/mL and 25 mg/mL, between 12 mg/mL and 25 mg/mL, between 12.5 mg/mL and 25 mg/mL, between 15 mg/mL and 25 mg/mL, and particularly 19 mg/mL. The anesthetic compositions disclosed herein, in limited doses, have the advantage of achieving higher maximum tolerated doses (depending on the plasma concentration of the anesthetic that would cause central nervous system and cardiovascular toxicity) and providing a rapid onset of action.

For clinical applications, in specific examples of the present disclosure, the free form of acetamide anesthetics may range from about 1% to about 50%, about 5% to about 40%, or about 10% to about 30%. The acetamide anesthetics retained in the lipid-based complex can serve as a drug reservoir, gradually releasing the acetamide anesthetics into the local environment in a manner that maintains a therapeutically effective dose in the local area. In some specific examples, after a single subcutaneous administration of the anesthetic composition of the present invention, the ropivacaine half-life is extended by at least 10 times compared to administration of ropivacaine solution. Furthermore, the duration of anesthetic effect of the anesthetic composition of the present invention is also significantly prolonged compared to ropivacaine solution.

The pharmaceutical composition disclosed herein exhibits significant therapeutically prolonged release properties and provides immediate and sustained pain reduction over a period postoperatively compared to clinically administered local anesthetics, reducing pain scores from 2 to 4 on a numerical pain rating scale of 0 to 10. For example, the pharmaceutical composition disclosed herein prolongs the half-life of locally administered liposomal anesthetics. Based on numerical pain rating scale scores, this composition demonstrates lower average pain at all times in the human body compared to free-state anesthetics or commercially available anesthetics, and significantly reduces total pain at 24 hours, 48 hours, 72 hours, 4 days, or 1 week postoperatively.

The lipid-based complex disclosed herein can be applied to the perineurium, surgical area, or surgical wound. The terms "postsurgical pain" and "post-operative pain" are used interchangeably throughout this document and refer to pain caused by various surgeries. In some specific cases, postoperative pain is caused by hernia repair surgery, urological surgery, hemorrhoid surgery, abdominal surgery, thoracic surgery, orthopedic surgery, including but not limited to hallux valgus surgery, vertebroplasty, acromioplasty, kyphoplasty, total knee or hip replacement surgery, obstetric and gynecological surgery, breast surgery, dental surgery, abdominoplasty, kidney transplantation, or any type of laparoscopic surgery.

The pharmaceutical composition disclosed herein can be administered by injection, infusion, or using standard syringes and needles. The pharmaceutical composition disclosed herein can be administered via subcutaneous, intradermal, or intramuscular routes.

In another specific instance, the pharmaceutical composition disclosed herein is administered for nerve block as a preventative treatment of pain conditions (e.g., preoperative administration to an individual in need of treatment for postoperative pain). In some specific instances, the pharmaceutical composition disclosed herein is administered for nerve block, such as quadratus lumborum block (QLB).

Peripheral nerve block involves directing medication to or within a peripheral nerve to reduce pain or numb it.

In another specific instance, the pharmaceutical composition disclosed herein is administered to the surgical area for regional block, such as: Mayo block for multiple foot nerves in hallux valgus surgery, Transversus Abdominis Plane Block (TAPB) for open laparotomy or tegumentotomy, and site-specific regional anesthesia techniques for total knee or hip replacement surgery.

The disclosure is further described below with reference to specific, non-limiting embodiments. Implements

The following experimental examples are used to disclose the preparation and properties of certain embodiments of the present invention. Example 1 Preparation of an anesthetic composition

1,2-Dimyristyl-sn-glycerol-3-phosphate choline (DMPC) was purchased from NOF Corporation (Tokyo, Japan) or Lipoid GmbH (Ludwigshafen, Germany). Cholesterol was purchased from Sigma-Aldrich (Darmstadt, Germany) or Dishman Pharmaceuticals and Chemicals (Gujarat, India), while ropivacaine was purchased from Apollo Scientific (Cheshire, UK) or Dishman Pharmaceuticals and Chemicals. All other chemicals were purchased from Sigma-Aldrich.

To prepare the lipid cake, ropivacaine and a lipid mixture were combined at a drug-to-phospholipid ratio (D:PL) of 1.458 μmol/μmol, i.e., phospholipid:cholesterol:ropivacaine = 2:1:2.9. The lipid and ropivacaine were mixed and dissolved in tert-butanol or a tert-butanol-water cosolvent (volume ratio 1:1) to form a liquid phase. This liquid phase was frozen and then freeze-dried for an additional day to obtain the lipid cake of the acetamide anesthetic.

A phospholipid:cholesterol ratio of 2:1 was weighed and dissolved in tert-butanol to prepare a lipid structure for the carrier control group. The resulting sample was frozen and then freeze-dried for another day to obtain lipid cakes for the carrier control group.

At a temperature not lower than room temperature (AT) (25°C), lipid cakes from the anesthetic or carrier control groups were hydrated separately with a buffer solution with a pH of 6.5 to 6.8 to form an anesthetic composition and a carrier control composition, respectively. Enzyme bonding efficiency and particle size distribution were then determined. Qualitative Analysis of the Anesthetic Composition

The binding efficiency of the samples prepared above will be determined using the methods described below. Equal 200 μL samples of each anesthetic composition will be centrifuged at 3000 x g for 5 min at 4°C to obtain a lipid-based complex. After removing the supernatant, the lipid-based complex will be resuspended to 200 μL. A reference standard for the absorbance of each drug (e.g., ropivacaine) will be established using a test drug solution of known concentration. The amount of drug in the original anesthetic composition and the lipid-based complex will be measured using a UV/Vis spectrophotometer. Binding efficiency is equivalent to the ratio of the amount of drug in the lipid-based complex to the amount of drug in the original anesthetic composition. The D:PL of the lipid matrix complex is calculated by multiplying the D:PL of the freeze-dried lipid cake by the bonding efficiency, and this is called the "final D:PL".

The particle size of each anesthetic component was measured using a laser diffraction spectrometer (LA-950V2, Horiba). The median diameter ( _D50 ) of the lipid-based complex, which was formed by hydrating freeze-dried lipid cakes with a pharmaceutically acceptable buffer solution (e.g., a 50 mM histidine buffer solution with a pH of 6.5), was measured.

The lipid-based complex in the anesthetic composition was determined to have a final drug-to-phospholipid ratio of approximately 1.32. The median diameter ( _D50 ) of the lipid-based complex particles in the anesthetic composition was approximately 5 to 10 micrometers. Example 2: Pain management in an adult individual following inguinal hernia repair surgery.

A phase I/II randomized, double-blind, comparator-controlled, dose-escalation trial was conducted to evaluate the safety, pharmacokinetics, and efficacy of a single local infiltration administration of the anesthetic composition disclosed herein (denoted as TLC590) compared to ^Naropin® in adults following inguinal hernia repair surgery.

This trial recruited approximately 64 evaluable participants who met the inclusion criteria and were divided into four cohorts. When compared to Naropin®, the dose escalation of a single postoperative dose of TLC590 was performed using a sequential dose level approach. The dose escalation was determined by the safety monitoring committee (SMC) by reviewing treatment-related adverse events (TEAEs) and all serious adverse events (SAEs).

The criteria for inclusion in the trial are as follows: 1. Able and willing to sign a written informed consent form; 2. Male or female aged 18 to 65 (inclusive); 3. Scheduled for a Liechtenstein inguinal hernia repair using a mesh anesthesia protocol and able to use this anesthesia protocol; 4. A Classification of Physical Status (ASA) score of 1 or 2; 5. Female participants must meet the following criteria to be considered suitable: not pregnant, not breastfeeding, not planning to become pregnant during the trial, and consenting to an acceptable form of contraception; or male participants must be sterilized or consent to use an effective method of contraception during the trial and for at least one week after administration of the blinded experimental drug; 6. Body mass index ≤ 35 kg/m².

Subjects were recruited to each group at a ratio of 3:1. Subjects in each group received a single dose of TLC590 or the active control drug [ ^Naropin® 150 mg; (0.5%, 5 mg/mL)] according to a randomization schedule and a dose escalation protocol (Figure 1).

To maintain objectivity, the investigational drug was managed and administered by an independent, non-blinded team, including the injector, pharmacist, and clinical trial specialist. Subjects, researchers, and all other staff members who directly interacted with subjects at the trial site, assessed safety and efficacy, and collected subject data remained blinded and were not allowed to communicate or discuss any trial information with the non-blinded team.

The design of arms and interventions is as follows: Arms

Experimental Group: TLC590 Group: TLC590 (Ropivacaine composition) is a sustained-release liposomal formulation of ropivacaine, a white aqueous suspension with a concentration of approximately 19 mg/mL.

Active control drug: ^Naropin® : ^Naropin® injection contains ropivacaine hydrochloride. Strength: 150 mg/30 mL (5 mg/mL), Size: 30 mL, filled in a single 30 mL vial. Interventions

Drug: TLC590 (Ropivacaine composition) TLC590 lipid cakes are resuspended in TLC590 resuspension solution to form the TLC590 anesthetic composition.

Drug: ^Naropin® is used for local infiltration to provide anesthesia for surgery and for pain relief in postoperative pain management. ^Naropin® 150 mg (0.5%, 5 mg/mL) x 30 mL ^. Other names: ^Naropin® , 0.5% injection solution.

The primary outcome measures are listed below: Safety and tolerability: (i) the number of serious adverse events and related adverse events following treatment (used to determine the maximum tolerated dose (MTD)) [timeframe: from screening to 30 days after surgical administration] and;

Secondary Outcome Measures are listed below: 1. Assess pain intensity at rest and during exercise using an 11-point Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (most imaginable pain). 2. Patient Global Assessment (PGA) (Poor, Average, Good, Excellent) for the pain management method. 3. Under-curve area (AUC) of the Numerical Rating Scale at rest and during exercise. 4. Cumulative proportion of participants who experienced no pain (defined as a resting NRS score of 0 or 1) at the specified time points. 5. Proportion of participants who experienced no pain (defined as a resting NRS score of 0 or 1) at the specified time points. 6. The cumulative percentage of subjects who did not use rescue analgesics at 12, 24, 36, 48, 72, and 96 hours post-surgery. 7. Time since the first use of rescue analgesics post-surgery. 8. Total usage of each type of rescue analgesic at 12, 24, 36, 48, 72, and 96 hours post-surgery. 9. Average daily usage of each type of rescue analgesic at 24, 48, 72, and 96 hours post-surgery. 10. Integrated analgesic score derived from the numerical pain rating scale score and rescue analgesic usage. 11. Cumulative proportion of subjects who did not use postoperative antiemetic treatment at 12, 24, 36, 48, 72, and 96 hours postoperatively. 12. Occurrence of all adverse events analyzed by severity and correlation. 13. Exposure-response relationship between pharmacokinetic parameters and numerical pain rating scale scores.

The changes in the above screening were analyzed statistically. Treatment with single local infiltration doses of TLC590 at doses of 190 mg, 380 mg, 475 mg, and 570 mg resulted in beneficial clinical responses at one or more of the trial endpoints shown above. Results

A total of 64 participants were randomly assigned to four groups. No serious adverse events or systemic toxicity (LAST) of the local anesthetic were observed during the study. All four TLC590 dose groups demonstrated similar safety and tolerability to the 150 mg ropivacaine. Even with the 570 mg TLC590 dose, the mean maximum plasma concentration of unbound ropivacaine was lower than that of the ropivacaine groups. The mean plasma concentration of each dose of TLC590 remained plateau for approximately 24 hours before decreasing. Its half-life (t½) was significantly longer than that of the ropivacaine group, and its maximum plasma concentration was less than one-fifth of the maximum plasma concentration (2.7 mg/mL) after infiltration with 300 mg ropivacaine solution (solution concentration 7.5 mg/mL) (Regional Anesthesia and Pain Medicine 23(2): 189-196, 1998) (Figure 1A). Compared to the ropivacaine group, all four doses of TLC590 reduced postoperative pain, estimated by the least square mean area under the pain curve of the Numerical Rating Scale. For 475 mg TLC590, compared with ropivacaine, the pain intensity during exercise or at rest achieved a sustained, statistically significant, and clinically meaningful reduction over time (all p>0.05; highest p=0.0131) (Figure 2); the pain reduction lasted for more than 168 hours compared with ropivacaine (Figure 3). The median time from first dose of rescue analgesia in the 475 mg TLC590 group was 3.2 times longer than in the ropivacaine group (42 hours vs. 13 hours). Among patients treated with 475 mg of TLC590, the majority (58.3%) did not use any rescue opioids during the trial. However, among those who did use rescue opioids, the median time to first postoperative opioid administration was four times longer than in the ropivacaine group (13 hours vs. 3.3 hours), and the average total opioid usage at 96 hours postoperatively was 54% less than in the ropivacaine group. Conclusion

TLC590 demonstrated similar safety and tolerability to ropivacaine, with no systemic toxicity events associated with local anesthetics. Compared to ropivacaine, it provided immediate and long-lasting pain reduction, thereby reducing or eliminating the need for opioids. Compared to those receiving clinically appropriate doses of the approved drug (ropivacaine), subjects receiving 475 mg of TLC590 showed advantages, with lower average pain at all times and a significant reduction in total pain over the 4-day postoperative period. Example 3 Pain Management in Adults Following Hallux Valgus Surgery

A phase II, randomized, double-blind, comparator-and-placebo-controlled trial was conducted to evaluate the safety, pharmacokinetics, and efficacy of a single postoperative administration of TLC590 via local infiltration to adult individuals following hallux valgus surgery, compared to ^Naropin® or bupivacaine and placebo.

This trial recruited approximately 223 eligible participants. The trial consisted of two parts: Part 1: Blinded pharmacokinetics of TLC590 and ^Naropin® . Approximately 48 participants were randomly assigned in a 1:1:1:1 ratio to receive treatment with 152 mg (8 mL) of TLC590, 190 mg (10 mL) of TLC590, 228 mg (12 mL) of TLC590, or 50 mg (10 mL) of ^Naropin® . Randomization was performed using a centralized interactive web response system (IWRS). Unblinded interim analysis was conducted to examine the safety, efficacy, and pharmacokinetics of the three TLC590 doses and ^Naropin® in Part 1 of the trial. Part 2: Efficacy and Safety of TLC590 relative to Bupivacaine and Placebo. Part 2 of this trial recruited approximately 150 participants who met all inclusion criteria and were randomly assigned in a 1:1:1 ratio to receive 228 mg of TLC590, bupivacaine, or a placebo, respectively. Randomization was assigned via a centralized interactive network response system. The trial design is shown in Figure 4.

The changes in the above screening were analyzed statistically. A beneficial clinical response could be summarized based on one or more of the above trial endpoints after treatment with single local infiltration doses of 152 mg, 190 mg and 228 mg of TLC590.

without

Figure 1 illustrates the clinical trial design for treating postoperative pain after hernia repair surgery using the anesthetic composition disclosed herein; Figure 1A shows a table comparing the maximum plasma concentration of ropivacaine after treating postoperative pain with the anesthetic composition disclosed herein at different specified dosages; Figure 2 illustrates the results of the clinical trial of the anesthetic composition disclosed herein, where AUC = area under the pain-time curve; LS = least squares; NPRS = Numerical Rating Scale for Pain; the least squares means (LS means) of the ANOVA model includes NPRS AUC as the response variable and treatment group as the fixed main effect; NPRS varies depending on the rescue drug. The use of the medication was adjusted using windowed worst observation carried forward (wWOCF) estimates; * indicates a comparison with ropivacaine, p < 0.05; Figure 3 shows the least squared mean of pain during movement at a dose of 475 mg of the anesthetic composition disclosed herein compared to ropivacaine, where missing data were estimated using last observation carried forward (LOCF) estimates, and rescue medications were estimated using windowed worst observation carried forward (LOCF) estimates; Figure 4 shows the clinical trial design for treating postoperative pain with the anesthetic composition disclosed herein after hallux valgus surgery.

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Claims (18)

A pharmaceutical composition for treating postoperative pain caused by hernia repair surgery, comprising: a lipid-based complex, wherein the lipid-based complex comprises an acetamide anesthetic and a lipid, wherein the molar ratio of the acetamide anesthetic to the lipid in the lipid-based complex is between 0.5:1 and 2:1, wherein the total amount of the acetamide anesthetic in the pharmaceutical composition ranges from 300 mg to 600 mg; and wherein the acetamide anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, articaine, prilocaine, and combinations thereof. The pharmaceutical composition as described in claim 1, wherein the pharmaceutical composition comprises 10 mg/mL to 30 mg/mL of the acetamide anesthetic. The pharmaceutical composition as described in claim 1, wherein the molar ratio of the acetamide anesthetic to the lipid in the lipid-based complex is between 0.5:1 and 1.5:1. The pharmaceutical composition as described in claim 1, wherein the lipid comprises a neutral saturated phospholipid. The pharmaceutical composition as described in claim 4, wherein the neutral saturated phospholipid comprises one or more saturated fatty acids, each saturated fatty acid independently comprising a carbon chain with no more than 18 carbon atoms. The pharmaceutical composition as described in claim 4, wherein the neutral saturated phospholipid is selected from the group consisting of dimyristylphosphatidylcholine (DMPC), 1,2-dilauryl-sn-glycerol-3-phosphate choline (DLPC), dipalmitoylphosphatidylcholine (DPPC), and combinations thereof. The pharmaceutical composition as described in claim 1, wherein the lipid is primarily composed of one or more neutral saturated phospholipids and one sterol. The pharmaceutical composition as described in claim 7, wherein the sterol is a cholesterol. The pharmaceutical composition as described in any of claims 1 to 8, wherein the median diameter of the lipid-based complex ranges from 5 micrometers to 200 micrometers. The pharmaceutical composition as described in any one of claims 1 to 8, wherein the lipid-based complex is prepared by the following steps: (a) providing a lipid cake comprising: the acetamide anesthetic; and the lipid; and (b) hydrating the lipid cake with a pharmaceutically acceptable buffer solution having a pH of 5.5 to 8.0 to form the lipid-based complex. A lipid-based complex is used in the preparation of a pharmaceutical composition for treating postoperative pain caused by hernia repair surgery in an individual requiring anesthesia. The lipid-based complex comprises a acetamide anesthetic and a neutral saturated phospholipid, wherein the neutral saturated phospholipid comprises saturated fatty acids, each saturated fatty acid independently comprising a carbon chain with fewer than 18 carbon atoms; wherein the acetamide anesthetic in the lipid-based complex is relative to the... The molar ratio of the neutral saturated phospholipids is between 0.5:1 and 2:1, wherein the median diameter of the lipid matrix complex ranges from 5 micrometers to 200 micrometers; and the total amount of the acetamide anesthetic ranges from 300 mg to 600 mg; and wherein the acetamide anesthetic is selected from the group consisting of lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, articaine, prilocaine, and combinations thereof. As described in claim 11, the total amount of the acetamide anesthetic is 475 mg. As described in claim 11, the pharmaceutical composition comprises 15 mg/mL to 25 mg/mL of the acetamide anesthetic. The use of a pharmaceutical composition as described in claim 1 for the preparation of a medicament for treating postoperative pain caused by hernia repair surgery, wherein the pharmaceutical composition is administered to an individual requiring anesthesia via nerve block, regional block, or infiltration anesthesia. As described in claim 14, the pharmaceutical composition is administered to an individual requiring anesthesia 30 minutes to 3 hours before or during surgery, wherein, based on a numerical pain assessment scale of 0 to 10, the pain score decreases by more than 2 over a period greater than 48 hours post-surgery. For the purpose described in claim 15, wherein the period is greater than 72 hours. For the purpose described in claim 15, wherein the period is greater than 96 hours. For the purpose described in claim 15, wherein the period is greater than 168 hours.